Approximately 150,000 Americans are treated for out-of-hospital cardiac arrest every year, but less than 5% survive with good neurological outcome. Induced hypothermia is the only therapy clinically proven to increase survival and improve neurological outcome of patients resuscitated from cardiac arrest. Although the optimal temperature range (32 to 34 [unreadable]C) is well established, critical gaps in our fundamental knowledge regarding the optimal time of onset, duration, and rate of rewarming have left clinicians guessing how to best apply this clinically effective intervention. Unfortunately, comprehensive optimization in clinical trials is profoundly limited by feasibility, time, and cost. To address these issues, we propose using a rat model of cardiac arrest to systematically evaluate two critical variables in the application of therapeutic hypothermia: optimal time of onset, and optimal duration of therapy. We hypothesize that therapeutic hypothermia after cardiac arrest is 1) equally effective when initiated between 1 and 8 hours after cardiac arrest, and 2) most effective when maintained for at least 48 hours. Our proposed Specific Aim will test these hypotheses using a 3 x 3 factorial study design that will compare therapeutic hypothermia (33.0 +/-1.0 [unreadable]C) initiated 1, 4, or 8 hours after resuscitation from cardiac arrest, maintained for 24, 48 or 72 hours, and rewarmed at a fixed rate of 0.25 [unreadable]C per hour. This study design will allow us to identify the optimal onset and duration of therapeutic hypothermia as well as potential interactions between the two parameters. Primary outcome parameters will include survival and Morris water maze behavioral function, and secondary outcome will be survival with good neurological function. Our structural surrogate outcome will be total brain atrophy based on morphometric quantification of total brain volume. A subset of rats will be instrumented for serial blood sampling to be used for future biomarker analysis. This study will, for the first time, systematically optimize the only proven therapy for patients resuscitated from cardiac arrest. The results will provide the fundamental knowledge that is urgently needed to design feasible, focused, and definitive clinical trials. In addition, this translational paradigm will be available to efficiently evaluate and optimize therapies that might be compared to or used in combination with therapeutic hypothermia. [unreadable] [unreadable] [unreadable]